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Genome-wide linkage analysis of chromogranin B expression in the CEPH pedigrees: implications for exocytotic sympathochromaffin secretion in humans

¹ Department of Medicine, University of California at San Diego
² Department of Psychiatry, University of California at San Diego
³ Center for Molecular Genetics, University of California at San Diego
⁴ Polymorphism Research Laboratory, University of California at San Diego
⁵ Veterans Affairs San Diego Healthcare System, San Diego, California 92161
⁶ Department of Medical Sciences, Clinical Chemistry, University Hospital, S-751 85 Uppsala, Sweden

Chromogranin B (CgB), a major member of the chromogranin/secretogranin family of catecholamine storage vesicle secretory proteins, plays both intracellular (vesiculogenic) and extracellular (prohormone) roles in the neuroendocrine system, and its biosynthesis and release are under the control of efferent sympathetic nerve traffic ("stimulus-transcription coupling"). To explore the role of heredity in control of CgB, we conducted a genome-wide linkage analysis of CgB release in 12 extended CEPH (Centre d’Etude du Polymorphisme Humain) pedigrees. Region-specific radioimmunoassays were used to measure five CgB fragments in plasma: CgB_1–16, CgB_312–331, CgB_439–451, CgB_568–577, and CgB_647–657. Substantial heritability, as measured by h²_r, was observed for three of the fragment concentrations, CgB_312–331, CgB_439–451, and CgB_568–577, which yielded h²_r estimates ranging from 0.378 (P = 0.002) to 0.910 (P < 0.0000001). Variance-component genome-wide linkage analysis with 654 microsatellite markers at 5 cM spacing identified a major quantitative trait locus for CgB_312–331 on chromosome 11q24-q25 with a maximum multipoint LOD score of 5.84. Significant allelic associations between markers in the region and CgB levels were also observed. Although the 2-LOD confidence interval for linkage did not include the CgB locus itself, known trans-activators of the CgB gene promoter, or prohormone cleaving proteases, examination of positional candidate loci within this region yielded novel and plausible physiological candidates for further exploration. Allelic variation in this region may thus influence effects of sympathetic outflow on target organs in humans.

chromogranin B; CHGB; chromaffin; catecholamine

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				T. A. Greenwood, F. Rao, M. Stridsberg, N. R. Mahapatra, M. Mahata, E. O. Lillie, S. K. Mahata, L. Taupenot, N. J. Schork, and D. T. O'Connor Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion Physiol Genomics, May 16, 2006; 25(3): 470 - 479. [Abstract] [Full Text] [PDF]